Precision-cut tissue slices: a novel ex vivo model for fibrosis research

Pathological scar formation, i.e. fibrosis, is characterized by a disproportionate production and deposition of extracellular matrix proteins in tissues resulting in loss of organ function. Fibrotic diseases account for up to 45% of worldwide mortality, yet there are no effective antifibrotic therapies currently available. To improve and accelerate antifibrotic drug discovery, there is an urgent need for reliable and reproducible (human) in vitro methods that reflect the cellular diversity that epitomize specific organs. This thesis delineates the successful development of a novel ex vivo/in vitro model for intestinal and renal fibrosis, namely precision-cut intestinal slices (PCIS) and precision-cut kidney slices (PCKS) prepared from murine, rat and human tissue. Our results demonstrated that the slices remain viable during culture and maintain their organ-specific phenotype. Moreover, in both PCIS and PCKS we observed that fibrosis could be induced by either culture activation or treatment with a profibrotic stimulus. Based on these findings, both models were subsequently used to evaluate the efficacy of various putative antifibrotic drugs. Using PCIS, we demonstrated that pirfenidone, LY2109761 and sunitinib could mitigate fibrogenesis on a gene level, warranting further evaluation of these compounds for the treatment of intestinal fibrosis. In addition, we demonstrated that IFNγ could be used to halt renal fibrogenesis. Furthermore, studies with precision-cut liver and intestinal slices revealed that rosmarinic acid elicited organ- and species-specific effects, illustrating the pressing need for good translational models for drug discovery. Taken together, this thesis delineates that precision-cut tissue slices can be used to unravel fibrosis and evaluate the antifibrotic potential of therapeutics